ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4096+1G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.4096+1G>A
Variation ID: 37565 Accession: VCV000037565.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43091434 (GRCh38) [ NCBI UCSC ] 17: 41243451 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 1, 2014 Oct 20, 2024 Apr 12, 2018 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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IVS11+1G>A
- Canonical SPDI
- NC_000017.11:43091433:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13050 | 14856 | |
LOC126862571 | - | - | - | GRCh38 | - | 1651 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (9) |
reviewed by expert panel
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Apr 12, 2018 | RCV000031146.20 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Oct 11, 2023 | RCV000048441.33 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 7, 2024 | RCV000162871.24 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000195364.21 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 23, 2014 | RCV000735546.9 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001354041.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 8, 2021 | RCV001554315.9 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2024 | RCV000585685.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 30, 2021 | RCV000790626.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 12, 2018)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Study: ENIGMA
Accession: SCV000783125.1 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
Comment:
Clinical data collected by the ENIGMA consortium demonstrates that the BRCA1 c.4096+1G>A variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 … (more)
Clinical data collected by the ENIGMA consortium demonstrates that the BRCA1 c.4096+1G>A variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant (Spurdle, unpublished data). This splice site variant has been proven to result in production of naturally occurring in-frame transcripts delta11q (Bonatti et al., 2006 - PMID: 17011978) and delta11 (Radice, unpublished data). Since no clinically relevant domain has been described in BRCA1 exon 11 (ENIGMA rules), the splicing alteration is compatible with the clinical data, and supports Class-3 classification. (less)
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Uncertain significance
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000693531.4
First in ClinVar: Mar 04, 2018 Last updated: May 23, 2021 |
Comment:
This sequence change occurs 1 base after exon 10 of the BRCA1 gene. This position is highly conserved in the human and other genomes and … (more)
This sequence change occurs 1 base after exon 10 of the BRCA1 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. Splicing assays have demonstrated that this variant results in the production of a shortened BRCA1 transcript lacking a large portion of exon 10, previously denoted exon 11, which is known as the BRCA1 delta11q isoform (PMID: 17011978). The delta 11q isoform has also been observed in control individuals and normal tissue (PMID: 8972225, 11359908, 11431698, 16943438). Moreover, functional studies in mice have indicated that they may retain some residual function of BRCA1 delta11q isoform (PMID: 8972225, 16943438, 11359908, 11431698). This variant is also known as IVS11+1G>A in the literature and it has been described in individuals affected with ovarian (PMID: 17011978) and breast cancer (PMID: 27328445). The mutation database ClinVar contains entries for this variant (Variation ID: 37565). In summary, this sequence change has been shown to impact mRNA splicing and is predicted to be deleterious. However, there are some indications that BRCA1 protein missing exon 10 may retain residual function. For these reasons, this variant has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296390.3
First in ClinVar: Sep 27, 2014 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00026 (3/11482 chromosomes in Southern European subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.00026 (3/11482 chromosomes in Southern European subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. The BRCA1 c.4096+1G>A variant has been proven to result in production of a naturally occurring in-frame transcript ‘delta 11’ (PMID: 17011978 (2006), ENIGMA Consortium (Evidence-based Network for the Interpretation of Germline Mutant Alleles, http://www.enigmaconsortium.org/)) and may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant. The 'delta 11' isoform of BRCA1 has been shown to be naturally occurring and one of the most abundant alternatively spliced isoforms found in normal tissues, such as breast and lymphocytes (PMID: 24569164 (2014)). This variant has also been observed in individuals with breast and/or ovarian cancer (PMIDs: 17011978 (2006), 21156238 (2010), 27328445 (2016), 29116469 (2018), 30675319 (2019), 32438681 (2020), and 32885271 (2021)) and prostate cancer (PMID: 29433453 (2018)). Functional studies have indicated that BRCA1 isoforms without BRCA1 exon 11 are partially or fully functional (PMID: 8972225 (1997), 11359908 (2001), 16943438 (2006)). Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jan 30, 2019)
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criteria provided, single submitter
Method: research
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Hereditary Breast Carcinoma
Affected status: yes
Allele origin:
germline
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A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center
Accession: SCV000914331.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Number of individuals with the variant: 1
Geographic origin: Brazil
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Likely pathogenic
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000210164.11
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
Comment:
Canonical splice site variant demonstrated to result in a shortened BRCA1 transcript lacking a large portion of exon 10, previously denoted exon 11, which is … (more)
Canonical splice site variant demonstrated to result in a shortened BRCA1 transcript lacking a large portion of exon 10, previously denoted exon 11, which is known as the delta11q isoform (Bonatti 2006); The resulting delta 11q isoform has also been observed in control individuals and normal tissue, therefore the clinical significance of this shortened transcript is indeterminate and this variant may confer risks lower than a typical BRCA1 pathogenic variant (Thakur 1997, Bonatti 2006, Colombo 2014); Observed in individuals with breast, ovarian, or prostate cancer (Bonatti 2006, Manguoglu 2010, Tung 2015, Brianese 2017, Ibrahim 2018, Slavin 2019, Santonocito 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4215+1G>A and IVS11+1G>A; This variant is associated with the following publications: (PMID: 25525159, 11162473, 17011978, 8972225, 16943438, 11359908, 24569164, 27328445, 21156238, 28588062, 21523855, 28152038, 26269718, 24131973, 29433453, 29116469, 16267036, 29907814, 29922827, 29446198, 25186627, 28726806, 26681312, 32885271, 32438681, 30728895, 30675319, 31209999, 15343273, 20104584, 22737296, 32322110, 31341520, 36331686, 35150867, 30720243, 35132179, 31159747, 28888541) (less)
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Uncertain significance
(Feb 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV004543871.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
ACMG codes applied following ENIGMA VCEP rules: PVS1_M (RNA), PM2_SUP
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Uncertain significance
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005058262.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004140625.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
BRCA1: PVS1:Strong, PS3:Moderate, PM2:Supporting, BS2
Number of individuals with the variant: 1
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Pathogenic
(Feb 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786121.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140538.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Uncertain significance
(May 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699108.4
First in ClinVar: Dec 26, 2017 Last updated: Jun 26, 2021 |
Comment:
Variant summary: BRCA1 c.4096+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: BRCA1 c.4096+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. Experimental evidence supports these predictions demonstrating the presence of a BRCA1 isoform that lacks a large portion of exon 10 (delta 10q) in a patient's cDNA (Bonatti_2006). Results indicated the delta 10q was more abundant than the full-length transcript and there was a quantitative difference between proband and control, with the patient showing a reduced amount of full-length transcript. Thus, increased amount of delta 10q coupled with decreased amount of full-length transcript is a potential disease mechanism attributed to this variant. However, the ability of the protein product derived from the delta 10q transcript to impact BRCA1 function was not demonstrated in this study. The isoform delta 10q would lack the Serine-Rich domain (InterPro). Alternatively spliced BRCA1 isoforms that affect exon 10 have been described in minor amounts in different human tissues (PMIDs: 9010228, 24569164) and mouse studies have indicated that they may retain some residual function (PMIDs: 8972225, 11359908, 16943438). The variant allele was found at a frequency of 1.2e-05 in 250952 control chromosomes (gnomAD). c.4096+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and other cancers (e.g. Bonatti_2006, Brianese_2018, Ibrahim_2018, Manguoglu_2010, Rebbeck_2018, Spugnesi_2016, Susswein_2016) but it was also detected in unaffected members of families reported with cases of breast cancer (e.g. Servais_2016, Slavin_2019). Co-occurrences with another pathogenic variant have been reported (UMD: BRCA2 c.8249_8250delAG, p.Lys2750AsnfsX13; ClinVar: BRCA1 unspecified variant). Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=6) and as uncertain significance (n=5, including ENIGMA expert panel). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325845.4
First in ClinVar: Sep 27, 2014 Last updated: Dec 11, 2022 |
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Uncertain significance
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003830125.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683149.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G>A nucleotide substitution at the +1 position of intron 10 of the BRCA1 gene. This variant is also known as IVS11+1G>A … (more)
This variant causes a G>A nucleotide substitution at the +1 position of intron 10 of the BRCA1 gene. This variant is also known as IVS11+1G>A and c.4215+1G>A. An RNA study found the variant enhanced the use of a naturally occurring alternative splice donor site in exon 10 (alternative transcript delta 11q), resulting in an in-frame deletion (PMID: 17011978, 24569164). This variant has been reported in at least six individuals affected with breast or ovarian cancer (PMID: 17011978, 21156238, 24131973, 25186627, 27328445, 29116469, 30728895, 32438681, 32885271, 32895300, 33801055), an individual affected with prostate cancer (PMID: 29433453) and in suspected hereditary breast and ovarian cancer families (PMID: 16267036, 24065114, 30675319, 31159747, 31209999). This variant has been identified in 3/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). It has also been reported that this variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant, presumably due to alternative splicing events that may ameliorate the deleterious impact of this variant (PMID: 32322110; ClinVar variation ID 37565). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Uncertain significance
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076454.14
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 10 of the BRCA1 gene. It is expected to disrupt RNA splicing. This variant is … (more)
This sequence change affects a donor splice site in intron 10 of the BRCA1 gene. It is expected to disrupt RNA splicing. This variant is present in population databases (rs80358178, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with BRCA1-related conditions (PMID: 17011978, 21156238, 27328445, 29116469, 29433453, 29446198, 32885271). ClinVar contains an entry for this variant (Variation ID: 37565). Experimental studies have shown that disruption of this splice site alters splicing of exon 10 (also referred to as exon 11 in the literature), resulting in loss of the full-length transcript, and increased expression of a shorter in-frame transcript that lacks a large portion of exon 10 (referred to as del11q) (PMID: 17011978, Invitae). This alternative in-frame transcript has been reported to occur naturally in healthy individuals (PMID: 24569164), and functional studies suggest that protein made from this transcript may retain residual function (PMID: 8972225, 11359908, 11431698, 16943438). The clinical significance of these findings is uncertain. A different variant (c.4096+3A>G), affecting the same consensus splice site, has been shown to result in the increased abundance of a naturally occurring BRCA1 isoform lacking exon 10, and a shortened in-frame splice variant that removes a large portion of this exon (PMID: 23239986). The shortened splice variants may retain residual function (PMID: 8972225, 16943438, 11359908, 11431698). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(May 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000213358.9
First in ClinVar: Mar 24, 2015 Last updated: Aug 11, 2024 |
Comment:
The c.4096+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the BRCA1 gene. Based on the majority … (more)
The c.4096+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the BRCA1 gene. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/250952) total alleles studied. The highest observed frequency was 0.003% (3/113500) of European (non-Finnish) alleles. This alteration has been reported in several triple-negative breast and ovarian cancer patients (Bonatti, 2006; Brianese, 2018; Lerner-Ellis, 2021), as well as multiple cohorts of ancestrally diverse of individuals undergoing genetic testing for hereditary cancer risk (Santonocito, 2020; Susswein, 2016; Tsaousis, 2019; Rebbeck, 2018). Of note, this alteration is also designated as IVS11+1G>A in published literature. This nucleotide position is highly conserved in available vertebrate species. RNA studies showed that this alteration leads to a partial exon 11 (CDS9) skipping event-termed Δ11q (Ambry internal data; Bonatti, 2006). However, these transcripts are also naturally occurring in humans and there is discordance among studies regarding the impact on the encoded proteins with respect to cellular localization and their role in hereditary cancer (Thakur, 1997; Huber, 2001; Colombo, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Uncertain significance
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199720.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Feb 13, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000053746.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Uncertain significance
(Sep 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228357.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PVS1_RNA(Moderate)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
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Uncertain significance
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004244007.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144971.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Near Eastern
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Pathogenic
(Apr 23, 2014)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863684.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591488.2 First in ClinVar: Apr 16, 2017 Last updated: Apr 13, 2021 |
Comment:
The c.4096+1G>A variant was identified in an individual with ovarian cancer from a hereditary breast and ovarian cancer family (Bonatti 2006). The variant was also … (more)
The c.4096+1G>A variant was identified in an individual with ovarian cancer from a hereditary breast and ovarian cancer family (Bonatti 2006). The variant was also identified in dbSNP (ID: rs80358178) “With pathogenic allele”, HGMD, LOVD, UMD (5X as a causal variant), and the BIC database (5X with clinical importance). The c.4096+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the 5' splice consensus sequence. Three in silico or computational prediction software programs (MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, RNA analysis of a patient with the variant determined that the variant resulted in a skipping of exon 11, with reduced expression of full-length transcript as compared to normal control DNA (Bonatti 2006). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Aug 08, 2021)
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no assertion criteria provided
Method: clinical testing
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Breast carcinoma
Affected status: yes
Allele origin:
germline
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Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001774837.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Invasive Breast Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Negative Her2 Receptor: Negative
Age: 40-49 years
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study. | Toss A | Diagnostics (Basel, Switzerland) | 2021 | PMID: 33801055 |
Implementing NGS-based BRCA tumour tissue testing in FFPE ovarian carcinoma specimens: hints from a real-life experience within the framework of expert recommendations. | Rivera D | Journal of clinical pathology | 2021 | PMID: 32895300 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for the Classification of Germline Sequence Variants in Risk Genes for Hereditary Breast and Ovarian Cancer. | Wappenschmidt B | Geburtshilfe und Frauenheilkunde | 2020 | PMID: 32322110 |
Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls. | Arvai KJ | Hereditary cancer in clinical practice | 2019 | PMID: 31341520 |
The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries. | Laitman Y | Human mutation | 2019 | PMID: 31209999 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
The effects of genomic germline variant reclassification on clinical cancer care. | Slavin TP | Oncotarget | 2019 | PMID: 30728895 |
BRCA mutation screening and patterns among high-risk Lebanese subjects. | Farra C | Hereditary cancer in clinical practice | 2019 | PMID: 30675319 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Male BRCA mutation carriers: clinical characteristics and cancer spectrum. | Ibrahim M | BMC cancer | 2018 | PMID: 29433453 |
BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation. | Brianese RC | Breast cancer research and treatment | 2018 | PMID: 29116469 |
Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action. | Smith LD | International journal of cancer | 2017 | PMID: 27997688 |
Germline mutations in DNA repair genes may predict neoadjuvant therapy response in triple negative breast patients. | Spugnesi L | Genes, chromosomes & cancer | 2016 | PMID: 27328445 |
The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. | Wang Y | Cancer research | 2016 | PMID: 27197267 |
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory. | Strom CM | PloS one | 2015 | PMID: 26295337 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. | Colombo M | Human molecular genetics | 2014 | PMID: 24569164 |
The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations. | Ricci MT | European journal of human genetics : EJHG | 2014 | PMID: 24065114 |
BRCA mutations and outcome in epithelial ovarian cancer (EOC): experience in ethnically diverse groups. | Safra T | Annals of oncology : official journal of the European Society for Medical Oncology | 2013 | PMID: 24131973 |
Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. | Wappenschmidt B | PloS one | 2012 | PMID: 23239986 |
Evolutionary constraint helps unmask a splicing regulatory region in BRCA1 exon 11. | Raponi M | PloS one | 2012 | PMID: 22615956 |
Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. | Manguoğlu E | Cancer genetics and cytogenetics | 2010 | PMID: 21156238 |
RNA-based analysis of BRCA1 and BRCA2 gene alterations. | Bonatti F | Cancer genetics and cytogenetics | 2006 | PMID: 17011978 |
Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-Delta11 isoform. | Kim SS | Molecular and cellular biology | 2006 | PMID: 16943438 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
Emerging roles of BRCA1 alternative splicing. | Orban TI | Molecular pathology : MP | 2003 | PMID: 12890739 |
Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. | Xu X | Nature genetics | 2001 | PMID: 11431698 |
Impaired DNA damage response in cells expressing an exon 11-deleted murine Brca1 variant that localizes to nuclear foci. | Huber LJ | Molecular and cellular biology | 2001 | PMID: 11359908 |
Expression profiles of BRCA1 splice variants in asynchronous and in G1/S synchronized tumor cell lines. | Orban TI | Biochemical and biophysical research communications | 2001 | PMID: 11162473 |
Localization of BRCA1 and a splice variant identifies the nuclear localization signal. | Thakur S | Molecular and cellular biology | 1997 | PMID: 8972225 |
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Text-mined citations for rs80358178 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.